The major goal of this application is to discover and develop medications for the treatment of substance abuse. Furthermore, we expect that the compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine, and amphetamine addiction and withdrawal. The initial objective of this proposal is to design, synthesize, and evaluate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) releasers. To date, most efforts towards an "agonist" therapy of stimulant addiction have concentrated on the discovery of selective DA uptake blockers. However increasing evidence shows that dual DA/5-HT selective or non-selective compounds may be required to "correct" the totality of stimulant-induced deficits during withdrawal. Experimental results published since the original grant application also suggests that releasers as a class may be effective synaptic agonist treatments. The optimal balance of activity between these three neurotransmitter systems is not known;however it is assumed that DAergic activity must be present with some combination of other activity. Thus, the primary objective of this application is to further develop the dual DA/5HT and non-selective "universal" releaser leads generated during the initial project period. These compounds may also be useful for treating other psychiatric disorders such as depression, anxiety, and stress. The target compounds will be small molecules that are expected to penetrate the CNS and have reasonable stability so that they will be useful medications and can be used as in vitro and in vivo probes. PUBLIC HEALTH RELEVANCE: Stimulant abuse and addiction continues to be a major societal problem the United States. Mounting evidence suggests that one of the best methods for combating stimulant addiction is the agonist approach in which drugs replace the biochemical deficits caused by chronic stimulant. Such an approach may be the only way to address the wide ranges of symptoms observed during withdrawal as well as the urge to relapse into drug taking behavior. Dual dopamine/serotonin releasers represent one approach to such agonist therapies and will be developed in this research program.